Zheng You, Liu Heng, Chen Yuxin, Dong Shaowei, Wang Fang, Wang Shengyi, Li Geng-Lin, Shu Yilai, Xu Fei
iHuman Institute, ShanghaiTech University, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Center for Excellence in Molecular Cell Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Center for Excellence in Molecular Cell Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
Neuron. 2022 Jan 19;110(2):237-247.e4. doi: 10.1016/j.neuron.2021.10.029. Epub 2021 Nov 11.
The KCNQ family (KCNQ1-KCNQ5) of voltage-gated potassium channels plays critical roles in many physiological and pathological processes. It is known that the channel opening of all KCNQs relies on the signaling lipid molecule phosphatidylinositol 4,5-bisphosphate (PIP2). However, the molecular mechanism of PIP2 in modulating the opening of the four neuronal KCNQ channels (KCNQ2-KCNQ5), which are essential for regulating neuronal excitability, remains largely elusive. Here, we report the cryoelectron microscopy (cryo-EM) structures of human KCNQ4 determined in complex with the activator ML213 in the absence or presence of PIP2. Two PIP2 molecules are identified in the open-state structure of KCNQ4, which act as a bridge to couple the voltage-sensing domain (VSD) and pore domain (PD) of KCNQ4 leading to the channel opening. Our findings reveal the binding sites and activation mechanisms of ML213 and PIP2 for neuronal KCNQ channels, providing a framework for therapeutic intervention targeting on these important channels.
电压门控钾通道的KCNQ家族（KCNQ1 - KCNQ5）在许多生理和病理过程中发挥着关键作用。已知所有KCNQ通道的开放都依赖于信号脂质分子磷脂酰肌醇4,5 - 二磷酸（PIP2）。然而，PIP2调节四种对调节神经元兴奋性至关重要的神经元KCNQ通道（KCNQ2 - KCNQ5）开放的分子机制仍 largely难以捉摸。在此，我们报告了在不存在或存在PIP2的情况下，与激活剂ML213复合测定的人KCNQ4的冷冻电子显微镜（cryo - EM）结构。在KCNQ4的开放状态结构中鉴定出两个PIP2分子，它们作为桥梁将KCNQ4的电压传感结构域（VSD）和孔道结构域（PD）耦合，导致通道开放。我们的研究结果揭示了ML213和PIP2对神经元KCNQ通道的结合位点和激活机制，为针对这些重要通道的治疗干预提供了框架。
